The identification of early changes in the HD brain at the cellular and molecular level is critical for understanding pathogenesis and developing treatments for the disease. Studies by us and others in HD brain, HD mice, and with in vitro cellular models of HD show that N-terminal fragments of mutant huntingtin containing the expanded polyglutamine tract can accumulate in the nucleus or cytoplasm of neurons and cause dysfunction and cell death. Affected neurons have nuclear and cytoplasmic inclusions, cytoplasmic vacuoles, and dystrophic neurites, and may be associated with activated microglia. N-terminal huntingtin interacts with proteins involved in diverse functions. Our overall hypothesis is that mutant huntingtin impairs function at multiple sites in neurons. The aims are: 1) To examine the regulation of huntingtin proteolysis and the accumulation of N-terminal mutant huntingtin products in neurons, 2) To determine the distribution of huntingtin and huntingtin fragments in the nucleus and a possible huntingtin interaction with a transcription repressor, 3) To determine huntingtin's association with the actin cytoskeleton and the effects of mutant huntingtin on actin- dependent cellular adhesion, 4) To examine the role of the pro-apoptotic proteins caspase 8 and BAX in mutant huntingtin induced cell death and 5) To explore the basis for microglia activation in HD. The results should help to elucidate the mechanisms underlying neuronal dysfunction and cell death in HD.